Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.

Antibiotics are a known cause of idiosyncratic drug-induced liver injury (DILI). According to the Centers for Disease Control and Prevention, the five most commonly prescribed antibiotics in the United States are azithromycin, ciprofloxacin, cephalexin, amoxicillin, and amoxicillin-clavulanate. We quantified the frequency of acute DILI for these common antibiotics in the All of Us Research Program, one of the largest electronic health record (EHR)-linked research cohorts in the United States. Retrospective analyses were conducted applying a standardized phenotyping algorithm to de-identified clinical data available in the All of Us database for 318,598 study participants. Between February 1984 and December 2022, more than 30% of All of Us participants (n = 119,812 individuals) had been exposed to at least 1 of our 5 study drugs. Initial screening identified 591 potential case patients that met our preselected laboratory-based phenotyping criteria. Because DILI is a diagnosis of exclusion, we then used phenome scanning to narrow the case counts by (i) scanning all EHRs to identify all alternative diagnostic explanations for the laboratory abnormalities, and (ii) leveraging International Classification of Disease 9th revision (ICD)-9 and ICD 10th revision (ICD)-10 codes as exclusion criteria to eliminate misclassification. Our final case counts were 30 DILI cases with amoxicillin-clavulanate, 24 cases with azithromycin, 24 cases with ciprofloxacin, 22 cases with amoxicillin alone, and < 20 cases with cephalexin. These findings demonstrate that data from EHR-linked research cohorts can be efficiently mined to identify DILI cases related to the use of common antibiotics.

Background: SLCO1B1 variants are known to be a strong predictor of statin-associated muscle symptoms (SAMS) risk with simvastatin. Methods: The authors conducted a retrospective chart review on 20,341 patients who had SLCO1B1 genotyping to quantify the uptake of clinical decision support (CDS) for genetic variants known to impact SAMS risk. Results: A total of 182 patients had 417 CDS alerts generated, and 150 of these patients (82.4%) received pharmacotherapy that did not increase risks for SAMS. Providers were more likely to cancel simvastatin orders in response to CDS alerts if genotyping had been done prior to the first simvastatin prescription than after (94.1% vs 28.5%, respectively; p < 0.001). Conclusion: CDS significantly reduces simvastatin prescribing at doses associated with SAMS.

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin‐associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long‐term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP‐C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1 , ABCG2 , and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin‐induced myopathy.

Within most electronic medical records, automated decision support helps health care providers reduce the frequency of adverse drug reactions. Historically, this decision support has been used to prevent drug-drug interactions (DDIs). More recently, the clinical and scientific communities have been moving toward the use of this approach to predict and prevent drug-gene interactions (DGIs). Genetic variation in cytochrome P450 2D6 (CYP2D6) is known to impact clinical outcome for many drugs, including opioids. Randomized trials have been initiated to assess the utility of CYP2D6 gene-based dosing versus usual care. We review the use of this approach to guide opioid prescribing in the post-operative setting.

Each of us reflects a unique convergence of DNA and the environment. Over the past 2 decades, huge biobanks linked to electronic medical records have positioned the clinical and scientific communities to understand the complex genetic architecture underlying many common diseases. Although these efforts are producing increasingly accurate gene-based risk prediction algorithms for use in routine clinical care, the algorithms often fail to include environmental factors. This review explores the concept of heritability (genetic vs nongenetic determinants of disease), with emphasis on the role of environmental factors as risk determinants for common complex diseases influenced by air and water quality. Efforts to define patient exposure to specific toxicants in practice-based data sets will deepen our understanding of diseases with low heritability, and improved land management practices will reduce the burden of disease.

Dysphagia megalatriensis is a rarely reported entity of cardiovascular dysphagia. Affected patients present with dysphagia to solid foods and regurgitation secondary to esophageal compression from an enlarged left atrium (LA). Here we report a case of a 68-year-old man with long standing atrial fibrillation who presented with chest pressure, bloating and dysphagia to solids. Esophagogastroduodenoscopy revealed a large area of extrinsic compression of the middle third of the esophagus that varied with cardiac contractions. Computerized tomography of the chest did not reveal any masses and transthoracic echocardiogram showed moderate LA enlargement. Based on those findings, a diagnosis of cardiac dysphagia was made. While severe LA enlargement is usually reported in cardiac dysphagia, our patient developed symptoms with moderate LA enlargement. Surgical intervention, dietary modifications, treatment of the underlying cause of LA enlargement and enteric tube feeding are available treatment options for cardiovascular dysphagia.

Objective We developed and evaluated Drug-Drug Interaction Wide Association Study (DDIWAS). This novel method detects potential drug-drug interactions (DDIs) by leveraging data from the electronic health record (EHR) allergy list. Materials and Methods To identify potential DDIs, DDIWAS scans for drug pairs that are frequently documented together on the allergy list. Using deidentified medical records, we tested 616 drugs for potential DDIs with simvastatin (a common lipid-lowering drug) and amlodipine (a common blood-pressure lowering drug). We evaluated the performance to rediscover known DDIs using existing knowledge bases and domain expert review. To validate potential novel DDIs, we manually reviewed patient charts and searched the literature. Results DDIWAS replicated 34 known DDIs. The positive predictive value to detect known DDIs was 0.85 and 0.86 for simvastatin and amlodipine, respectively. DDIWAS also discovered potential novel interactions between simvastatin-hydrochlorothiazide, amlodipine-omeprazole, and amlodipine-valacyclovir. A software package to conduct DDIWAS is publicly available. Conclusions In this proof-of-concept study, we demonstrate the value of incorporating information mined from existing allergy lists to detect DDIs in a real-world clinical setting. Since allergy lists are routinely collected in EHRs, DDIWAS has the potential to detect and validate DDI signals across institutions.

Advancements in clinical informatics and translational genomics are changing the way we practice medicine. Automated decision support currently helps providers adjust prescribing patterns to reduce the likelihood of QT prolongation based upon drug-drug interaction. A similar approach is being explored for drug-gene interaction. Like many adverse drug reactions, QT prolongation can be influenced by variability in genetic factors. However, drug-induced QT prolongation can occur in the absence of any known ion channel gene abnormalities. We therefore review differences between congenital long QT syndrome and drug-induced long QT syndrome, and we underscore the need for decision support that integrates EKG data.

Introduction: Atorvastatin is commonly prescribed to prevent cardiovascular disease; however, long-term adherence can be eroded by statin associated musculoskeletal symptoms (SAMS). Genetic variants in SLCO1B1 are associated with SAMS in patients using simvastatin; the association of these variants with adherence or SAMS has been less well characterized for atorvastatin. Methods: We tested the association between a loss of function genetic variant in SLCO1B1 and atorvastatin discontinuation in a large multi-specialty group practice. Using the electronic medical record (EMR) at Sanford Health, we defined a retrospective cohort of 8453 patients who were tested for SLCO1B1*5 (rs4149056, Val174Ala) through routine clinical care. Patients were included if they had received an atorvastatin prescription prior to genetic testing and had valid SLCO1B1 results. Patients were classified as discontinued (or not) based on their active medication list at the time of genetic testing. Clinical characteristics including demographics, diagnosis codes, smoking status, concomitant medications, and laboratory values for renal function and all creatine kinase (CK) values prior to testing, were extracted from the EMR. A Kruskal-Wallis test was used to compare longitudinal CK values vs. discontinuation. Logistic regression was used to test the relationship between SLCO1B1*5 and atorvastatin discontinuation for any reason. Results: There were 1752 patients available for analysis (mean age 64 years, 44% female, 2% non-Caucasian, 89% primary prevention indication). 1025 (58%) discontinued atorvastatin prior to SLCO1B1 testing. The number of SLCO1B1*5 alleles was associated with atorvastatin discontinuation (odds ratio per allele = 1.22, 95% confidence interval = 1.004 - 1.47, p = 0.04). Among the 495 patients with available CK levels, atorvastatin discontinuation was associated with higher mean CK levels than those who continued (Kruskal-Wallis test, p = 0.02). Conclusions: Atorvastatin discontinuation is common in real world patients at risk for cardiovascular disease. Carriers of SLCO1B1*5 are at increased risk for premature atorvastatin discontinuation - an effect which may reflect an excess risk of statin myopathy.

Aim: To examine the impact ofCYP2C19genotype on selective serotonin reuptake inhibitor (SSRI) prescribing patterns.Patients & methods: Observational cohort containing 507 unique individuals receiving an SSRI prescription with CYP2C19 genotype already in their electronic medical record. Genotype was distributed as follows: n=360 (71%) had no loss of function alleles, 136 (26.8%) had one loss of function allele and 11 (2.2%) had two loss of function alleles. Results & conclusion: For poor metabolizers exposed to sertraline, citalopram or escitalopram, providers changed prescribing patterns in response to alerts in the electronic medical record by either changing the drug, changing the dose or monitoring serial EKGs longitudinally. For intermediate metabolizers exposed to sertraline, citalopram or escitalopram, no alert was needed (mean QTc=440.338ms [SD=31.1273] for CYP2C19*1/*1, mean QTc=440.371ms [SD=29.2706] for CYP2C19*1/*2; p=0.995).

Delayed anaphylaxis to mammalian meat is a newly recognized IgE-mediated syndrome associated with Lone Star tick bites. IgE-mediated anaphylaxis classically occurs within one hour of exposure to the allergen, which is typically a protein epitope. However, in this disease, circulating antibodies to a carbohydrate, alpha-gal (galactose-alpha-1,3-galactose), stimulate the anaphylactic cascade with hives, diarrhea, abdominal cramps, respiratory distress and anaphylactic shock developing after ingestion of beef, pork or lamb meat. The delayed onset of symptoms three to six hours after ingestion of meat is unique. Recognition and understanding of this disease is important for treating and educating patients with suggestive symptoms. Avoidance of red meat is the recommended therapy.

In this report, we discuss an unusual case of pulmonary lymphomatoid granulomatosis (LYG), a rare form of angiocentric and angiodestructive lymphoproliferative disorder. This disease is thought to be caused by Epstein-Barr virus-induced lymphoproliferation. A 39-year-old male with no signi ficant past medical history presented with flu-like symptoms. Upon further evaluation, laboratory studies noted pancytopenia, and a chest X-ray showed bilateral nodular densities. A computerized tomography (CT) scan demonstrated bilateral pulmonary nodules and splenomegaly. A biopsy of the pulmonary nodules revealed polymorphous, CD3-positive, lymphohistiocytic, inflammatory in filtrate within the walls of the arterioles and venules with associated necrosis. This histopathology is consistent with LYG. The patient was started on a regimen of rituximab, and he signi ficantly improved within a few weeks after the initiation of therapy, including resolution of the pancytopenia. A repeat CT scan showed the decreased size of the lung nodules. This case was histopathologically consistent with LYG but negative for Epstein-Barr virus ribonucleic acid. This demonstrates the potential for diagnostic difficulty in a case presentation of multiple pulmonary nodules. Extensive work-up for neoplastic, infectious, inflammatory, and autoimmune etiologies needs to be done in such cases. A prompt diagnosis of LYG is necessary for optimal management and improved patient outcomes.

INTRODUCTION:The convergence of biomedical informatics and translational genomics is changing the way we practice. Primary care will play a pivotal role in this transformation. We therefore sought to assess general knowledge about genetic testing among outpatient internal medicine providers, and the patients that they serve across a five state region in the Midwest.METHODS:One thousand take-home paper surveys were created and distributed to internal medicine patients at 13 Midwestern clinics. Sixty-two electronic surveys were also created and distributed to internal medicine providers at these same clinics. Questions assessed knowledge, interest, and comfort with genetic testing as well as the role of genetic counselors. Differences in response based on physician characteristics were compared using a Chi-squared analysis.RESULTS:In general, patients cared for in internal medicine clinics expressed an understanding of both content (75 percent) and rationale (81 percent) for genetic testing. Patients are open to hearing about genetic risks that could affect their health (88 percent) even if their visit was scheduled for a different reason. In these same clinics, providers expressed a strong understanding of the purpose of genetic testing (88 percent). However, providers were not confident in responding to questions about the impact of genetic testing on disease susceptibility (25 percent). Providers were more confident answering questions about genetic variability in drug response (46 percent). In general, outpatient internal medicine providers feel comfortable referring patients to genetic counselors to assess disease risk (88 percent) and they believe genetic testing is relevant to their practice (75 percent).CONCLUSIONS:In our Midwestern sample, we found that both patients and providers express interest in learning more about genetic testing in the context of primary care. Patient and physician responses indicate a role for genetic counselors in helping our patients understand and interpret genetic test results.

Red blood cell transfusions have been cited as one of the most overused therapeutic interventions in the USA. Excessively aggressive transfusion practices may be driven by mandatory physician notification of critical hemoglobin values that do not generally require transfusion. We examined the effect of decreasing the critical value of hemoglobin from 8 to 7 g/dL at our institution. Along with this change, mandatory provider notification for readings between 7 and 8 g/dL was rescinded. Transfusion rates were compared retrospectively during paired 5-month periods for patients presenting in three key hemoglobin ranges (6.00-6.99, 7.00-7.99, and 8.00-8.99 g/dL). A change in transfusion practices was hypothesized in the 7-8 g/dL range, which was no longer labeled critical and for which mandated physician calls were rescinded. Transfusion rates showed a statistically significant 8% decrease (P≤0.0001) during the 5-month period post change in our transfusion practices. This decrease in the 7.00-7.99 g/dL range was significantly greater than the 2% decrease observed in either the 6-6.99 g/dL (P=0.0017) or 8-8.99 g/dL (P≤0.0001) range. Cost savings of up to $700,000/year were extrapolated from our results showing 491 fewer units of red blood cells transfused during the 5-month post change. These cost savings do not take into account the additional impact of complications associated with blood transfusions.

Primary care is changing rapidly. The wide-scale expansion of electronic medical records is redefining the way we approach chronic disease management, and automated decision support is increasingly being leveraged to reduce risk and optimize quality. Many of these interventions are now beginning to integrate genomic data. We explore the convergence of these 2 forces (expansion of clinical informatics and integration of translational genomics), and we highlight several applications where these forces are helping our patients avoid potentially preventable events. Because gene-environment interactions are dynamic, the utility of gene-based decision support varies over time. Primary care providers will serve a key role as our patients navigate these changes.